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Clinical Use of Dexmedetomidine

Clinical Use of Dexmedetomidine. Charles E. Smith, MD Professor of Anesthesia Director, Cardiothoracic Anesthesia MetroHealth Medical Center Case Western Reserve University Cleveland, Ohio, USA October 7, 2003. Objectives. Pharmacology of dex alpha 2 agonist

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Clinical Use of Dexmedetomidine

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  1. Clinical Use of Dexmedetomidine Charles E. Smith, MD Professor of Anesthesia Director, Cardiothoracic Anesthesia MetroHealth Medical Center Case Western Reserve University Cleveland, Ohio, USA October 7, 2003

  2. Objectives • Pharmacology of dex • alpha 2 agonist • Molecular targets + neural substrates • locus caeruleus • natural sleep pathways • Clinical paradigms for use of dex in anesthesia • sedation + analgesia w/o resp depression • attenuation of tachycardia • smooth emergence + weaning from mech vent

  3. Pharmacology • Establish and maintain adequate drug concentration at effector site to produce desired effect • sedation • hypnosis • analgesia • paralysis • Predict the time course of drug onset + offset

  4. Pharmacodynamics • Relationship between drug conc + effect • Interaction of drug with receptor • Receptor • cell component • interacts with drug • biochemical change • Examples of receptors: • AchR, GABA, opioid,  +  adrenergic

  5. Receptors • Coupled to ion channels • neural signaling, 2nd messenger effects • Drug effects at receptor • agonist, antagonist or mixed effects • stereospecificity, racemic mixture of isomers • Receptor alterations • upregulated or downregulated (e.g., CHF) •  or  number (e.g., burns, myasthenia gravis)

  6. Pharmacodynamics • Sedation/hypnosis • Anxiolysis • Analgesia • Sympatholysis (BP/HR, NE) • Reduces shivering • Neuroprotective effects • No effect on ICP • No respiratory depression

  7. Pharmacokinetics • Rapid redistribution: 6 min • Elimination half-life: 2 h • Vd steady state: 118 L • Clearance: 39 L/h • Protein binding: 94% • Metabolism: biotransformation in liver to inactive metabolites + excreted in urine • No accumulation after infusions 12-24 h • Pharmacokinetics similar in young adults + elderly

  8. Clonidine Selectivity: 2:1 200:1 t1/2  8 hrs1 PO, patch, epidural Antihypertensive Analgesic adjunct IV formulation not available in US Dexmedetomidine Selectivity: 2:1 1620:1 t1/2  2 hrs Intravenous Sedative-analgesic Primary sedative Only IV 2 available for use in the US 2 Agonists

  9. Mechanism for the Hypnotic Effect • Hyperpolarization of locus ceruleus neurons –2A-Adrenoreceptor subtype • Activation of K+ channels • Inhibition of Ca++ channels • Inhibition of adenylyl cyclase •  Firing rate of locus caeruleus neurons •  Activity in ascending noradrenergic pathway

  10. Restorative Properties of Sleep • Activates natural sleep pathways • Increased rate of healing • Promotes anabolism • Facilitates growth hormone release • Counteracts catabolism • Inhibits cortisol release • Inhibits catecholamine release

  11. Harmful Effects of Sleep Deprivation •  pressor response to sympathetic stimulation • Impaired CV response to positioning change •  BP, HR + urine norepinephrine • Immune dysfunction •  ability of lymphocytes to synthesize DNA •  leukocyte phagocytic activity •  interferon production by lymphocytes • Cognitive dysfunction • Impaired memory, communication skills • Impaired decision-making • Confusional state [ICU]: apathy, delirium

  12. Mechanisms for Analgesic Effect Opioids 2 Agonists Peripheral nociceptors  inflammation [e.g., bradykinin, other kinins] Inhibit sympathetic- mediated pain Primary afferent neurons Inhibit release of SP and glutamate Inhibit release of SP and glutamate Second order neurons Inhibit firing Inhibit firing Subcortical + cortex Decrease emotive aspects Decrease emotive aspects Descending inhibitory pathways Activate PAG; activate noradrenergic pathways Disinhibit A5/A7 noradrenergic pathways

  13. Dex: Package Insert Info • Indications • Sedation of intubated and ventilated patients during treatment in an ICU setting x 24 h • Contraindications • Caution in patients with advanced heart block, severe ventricular dysfunction, shock • Drug interactions • Vagal effects can be counteracted by atropine / glyco • Clearance is lower w hepatic impairment • Withdrawal sx after discontinuation: not seen after 24 h use • Adrenal insufficiency: no effect on cortisol response to ACTH

  14. Bariatric surgery Sleep apnea patients Craniotomy: aneurysm, AVM [hypothermia] Cervical spine surgery Off-pump CABG Vascular surgery Thoracic surgery Conventional CABG Back surgery, evoked potentials Head injury Burn Trauma Alcohol withdrawal Awake intubation Clinical Uses of Dex in Anesthesia

  15. Sleep Apnea Patients Anesthesia considerations • Morbid obesity, at risk for aspiration • Difficult IV access • Systemic + pulm HTN, cor pulmonale • Postop airway obstruction + ventilatory arrest with anesthetic drugs •  upper airway muscle activity • inhibition of normal arousal patterns • upper airway swelling from laryngoscopy, surgery, intubation Dexmedetomodine • Anesthetic adjunct to minimize opioid + sedative use Ogan OU, Plevak DJ: Mayo Clinic; www.sleepapnea.org

  16. Gastric Bypass Surgery Patients Morbidly obese patients • Prone to hypoxemia • Sleep apnea is common • Respiratory depression w opioids Dexmedetomidine, 0.1 to 0.7 ug/kg/hr, prospectively studied in 32 pts •  opioid use in dex group • 1 pt in control gp needed reintubation • Dex pts more likely to be normotensive w  HR Craig MG et al: IARS abstract, 2002. Baylor

  17. Dex Improves Postop Pain Mgt after Bariatric Surgery RCT, n= 25. Dex started at 0.5 to 0.7 ug/kg/hr 1 hr prior to end of surgery [vs.saline]. Double- blind • Infusion adjusted according to need • Dex continued in PACU • PACU pain control with PCA Dexmedetomidine • Morphine use  in dex gp (P < 0.03) • Pain score better in dex gp: 1.8 vs 3.4 (P < 0.01) • % time pain free in PACU  in dex gp: • 44% vs 0 (P < 0.002) • Better control of HR in dex gp Ramsay MA, et al: Anesthesiology, 2002: A-910 and A-165. Baylor

  18. Craniotomy for Aneurysm / AVM Anesthesia considerations • Smooth induction + emergence • Prevent rupture • Avoid cerebral ischemia • Hypothermia (33 oC)  CMRO2, CBF, CBV, CSF, ICP Dexmedetomodine •  sympathetic stimulation •  or no change in ICP •  shivering w/o resp depression • Preserved cognitive fct • reliable serial neuro exams Doufas AG et al: Stroke 2003;34. Louisville, KY

  19. Coronary Artery Surgery Patients Herr study, n=300: Dex vs. controls [propofol] • RCT, dex started at sternal closure, 0.4 ug/kg/hr after loading dose, and 0.2 to 0.7 ug/kg/hr for 6- 24 hrs after extubation • Ramsay > 3 before extub, Ramsay 2 after extub Dexmedetomidine • Faster time to extub in dex gp • by 1 hr • 94% did not require propofol • 70% did not require morphine • (vs. 34% controls) • Dex pts had less Afib (7 vs 12 pts) Herr DL: Crit Care Med 2000;28:M248. Washington Hospital

  20. CABG and Lung Disease Lung Disease • Often delays tracheal extubation • RCT, n= 20. Dex started at end of surgery, 0.2 to 0.7 ug/kg/hr, + continued 6 hr after extubation vs. controls (propofol) • Ramsay > 3 before extub, Ramsay 2 after extub Dexmedetomidine • Faster time to extub: • 7.8 + 4.6 h v. 16.5 + 11.8 h • No difference in PaCO2 between gps 30 min after extub: 37.9 v. 34.9 mmHg Sumping ST: CCM 2000;28:M249. Duke

  21. Thoracotomy + Thoracoscopy Thoracotomy + thoracoscopy patients • COPD, pleural effusion, marginal pulmonary fct •  pCO2 +  pO2 with opioids for analgesia • Thoracic epidural: mainly for thoracotomy • Dex: mainly for thoracoscopy Dexmedetomidine • Patients are arousable, but sedated • Does not  ventilatory drive • Greatly  need for opioids • Alternative to thoracic epidural • Continue after extubation

  22. Vascular Surgery Vascular surgery patients • Usually at risk for CAD, ischemia, HTN, tachycardia • Dex attenuates periop stress response • Dex attenuates  BP w AXC, especially thoracic aorta Dexmedetomidine • RCT, n=41. Dex continued 48 hr postop • HR  in dex gp at emergence • 73 + 11 v. 83 + 20 bpm • Better control of HR in dex gp • Plasma NE levels  in dex gp Talke et al: Anesth Analg 2000;90:834. Multicenter

  23. Meta- Analysis of Alpha-2 Agonists 23 trials, n=3395. • All surgeries:  mortality + ischemia • Vascular:  MI + mortality • Cardiac:  ischemia • Cardiac:  BP (more hypotension) Conclusions: • Not class 1 evidence yet, but trials look promising • Especially vascular surgery Wijeysundera, Am J Med 2003;114:742. Univ of Toronto

  24. Other Surgical Procedures • Neck + back surgery • Dex causes minimal effect on SSEP monitoring • Smooth emergence, especially cervical spine • Easy to evalute neuro fct prior to + after extub • Abdominal surgery • Dexmedetomidine provides analgesia without respiratory depression • Especially useful in elderly undergoing colon resections, TAH, + other stressful procedures

  25. Perioperative Dex Infusion Protocol Example: 70 kg patient. Assess BP, HR, volume status Hypovolemic Normovolemic Monitor BP/HR throughout If bradycardia, infusion Volume preload500 to 1000 cc LR 2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml Start at 40 mL/hr Usual load: 25 to 35 ug or 6 to 9 mL over 10-15 min Stop load if  HR Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr] Dex=dexmedetomidine.

  26. Considerations With AnesthesiaUse of Dexmedetomidine • Dilute in 0.9% saline: 4 mcg/mL • Requires infusion pump: mcg/kg/h • Transient HTN: with rapid bolus • Hypotension may occur, especially if hypovolemia •  HR (attenuation of tachycardia): usually desirable •  conc of inhaled agents: BIS monitoring • Continue infusion after extubation for 30 min [PACU] • L + D: not studied • Pediatrics: abstracts + case reports [Lerman, Toronto] • Geriatrics: more hypotension + bradycardia:  dose

  27. Use of Dexmedetomidine in the Burn Unit • 2 agonist effect assists in the management of burn patients; blunts catecholamine surge • Use in intubated and non-intubated burn patients • Administer as a standard load once patient is normovolemic (range: 0.4 to 0.7 mcg/kg/hr) •  dose for less severe burns and non-intubated patients • 0.2 to 0.4 mcg/kg/hr for routine burn care • outpatient dressing changes, instead of ketamine

  28. Alcohol Withdrawal and Trauma • Trauma often occurs in males who are intoxicated • Trauma pt may experience agitation and is at risk for exacerbating underlying injuries (e.g., SCI) • Benzodiazepines typically used • Intubation and ventilation often required if extreme agitation • Dexmedetomidine is an alternative • Spontaneous breathing • Hemodynamic stability • Adequate sedation • Prevention of autonomic effects of withdrawal • Pain control

  29. Summary • Goal is to establish + maintain adequate drug conc at effector site to produce desired effect • Dex can help optimize anesthesia via: • Sedation, analgesia +  sympathetic activity • Attenuation of stress response +  HR • Smooth emergence + tracheal extubation • Unique mechanism of action on natural sleep pathway permits sedation + analgesia w/o respiratory depression • Adjunct agent of choice for many surgeries

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